Table 2.
Summary of reported cases of hypercalcemia after denosumab discontinuation
| Number of pat | Reference | Age, sex | Indication | DMAb dose, frequency, duration | Reason for discontinuation | Delay to hypercalcemia diagnosis | Ca/P values | BTMs, PTH, FGF23 | Clinical consequences | Hypercalcemia treatment |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Boyce et al.; J Bone Miner Res.2012;27:1462 [8] | 9 years, M | Fibrous dysplasia, expanding lesion | 0.9 mg/kg, 1×/month, 7 doses | Femoral fracture, theoretical risk of delayed fracture healing | 2 months | 4.5 mmol/l; P normal | P1NP > 1000 μg/l, CTX ≥ 5000 ng/l, PTH suppressed | 5 days vomiting | Rehydration, repeated bisphosphonate (pamidronate), calcitonin |
| 1 | Grasemann et al.; J Clin Endocrinol Metab.2013; 98:3121 [9] | 8 years, F | Juvenile Paget’s disease | 0.5 mg/kg, 1×/6 weeks, 2 doses | Improvement clinical condition | 7 weeks | Ca 4.07 mmol/l | Polyuria, nausea, constipation | Bisphosphonate (pamidronate) | |
| 1 | Gossai et al.; Pediatr Blood Cancer.2015; 62:1078 [5] | 10 years, F | Metastatic giant cell tumor of bone | 120 mg, 4×/month, then 1×/month, 24 months (28 doses) | Decrease in tumor size and improved pain; risk of osteopetrosis | 5 m | Ca 4.15 mmol/l; P normal | PTH suppressed | Nausea, vomiting, acute kidney injury | Aggressive hydration, calcitonin, bisphosphonate (pamidronate), corticosteroids, restart DMAb |
| 1 | Setsu et al.; J Bone Miner Metab.2016; 34:118 [6] | 10 years, M | Unresectable giant cell tumor of bone | 120 mg, 1×/month, 14 months (12 doses) | Development of sclerotic changes in the growth plates | 4 months | tCa 3.8 mmol/l; iCa 1.68 mmol/l; P 0.77 mmol/l | PTH suppressed (0.2 pmol/l) # | Nausea, fatigue, alkalosis, renal dysfunction, dehydration, sinus bradycardia with normal QTc | Saline hydration, furosemide, corticosteroid, calcitonin, bisphosphonate (zoledronate, 2×) |
| 10 | Hoyer-Kuhn et al.; J Musculosckelet Neuronal Interact.2016; 16:24 [3] | 5–11 years, 7 M and 3 F | Osteogenesis imperfecta | 1 mg/kg, 1×/3 months, 1 years | Primary endpoint of the study | Not specified | iCa 1.4 mmol/l | Osteocalcin and PTH detectable | No clinical significance | |
| 1 | Koldkjær Sølling et al.; Osteoporos Int.2016; 27:2383 [4] | 67 years, F | Osteoporosis | 60 mg, 1×/6 months, 10 years | End of clinical trial (FREEDOM) | 6 months | tCa 3.1 mmol/l; iCa 1.64 mmol/l; P 0.94 mmol/l | PTH suppressed (1.6 pmol/l) | No symptoms | Calcium-vit D substitution discontinuation; hyperhydration |
| 1 | Boyce; Curr Osteoporos Rep.2017; 15:283 [10] | 23 months, M | Osteogenesis imperfecta type VI | 1 mg/kg, 1×/month, 12 months | Not specified | 2 months | Hypercalcemia (not specified) | Not assessed | Not specified | Bisphosphonate (pamidronate) |
| 3 | Uday et al.; J Clin Endocrinol Metab.2018; 103:596 [7] | 15 years, M; 14 years, F; 40 years, M | Giant cell tumor of bone | 120 mg, 1×/week first month, then 1×/month, 3.6 years, 1.3 years, 4 years respectively | ONJ; end of treatment; femoral cortical stress reaction | 7 months; 6 months; 5.5 months | cCa 3.1 mmol/l; cCa 3.4 mmol/l; cCa 4.3 mmol/l; P normal | CTX 3070 ng/l, PTH suppressed | Nausea, vomiting, acute kidney injury, bone pain, inferior members paresthesia | Hyperhydration, furosemide, bisphosphonate (pamidronate) |
| 2 | Trejo et al.; J Musculosckelet Neuronal Interact. 2018; 18:76 [15] | 2.7 years M; 1.9 years M | Osteogenesis imperfecta type VI | 1.3 years, 2.6 years respectively | Study protocol | 12 weeks; 9 weeks | iCa 1.54 mmol/l; iCa 1.62 mmol/l | PTH suppressed, hypercalciuria, CTX elevated | Nephrocalcinosis | Bisphosphonate (pamidronate) |
| 1 |
Tjelum et al.; Ugeskr Laeger.2018; 180(45) [14] |
77 years, F | Osteoporosis | 60 mg, 1×/6 months, for 2 years | Hypoparathyroid hypercalcemia and renal dysfunction | 6 months | Not specified | Hypercalcemia, PTH suppressed | Dehydration, severely impaired kidney function secondary to diarrhea | Rehydration |
| 1 | Roux et al.; Bone.2019; 120:482 [12] | 54 years, F | Adjuvant therapy for breast cancer (clinical trial); antiaromatase | 120 mg, 1×/month for 6 months, then quarterly, total 5 years | Absence of bone metastases; end of clinical trial | 4 months | cCa 3.1 mmol/l, P 1.3 mmol/l | CTX 669 ng/l, osteocalcin 64 μg/l | Polyuro-polydypsic syndrome, asthenia, severe constipation, diffuse pain in arms | Rehydration, bisphosphonate (pamidronate) 1×/month for 3 months |
| 1 | Uchida et al.; Endocr J. 2019. doi: 10.1507 [13] | 47 years, F | Adjuvant therapy for breast cancer (clinical trial); antiaromatase | 120 mg, 1×/month for 6 months, then quarterly, total 5 years | Absence of bone metastases; end of clinical trial | 6 months | cCa 3.59 mmol/l, P 1.29 mmol/l | NTX 510 nmol BCE/ mmol creat, PTH 2.43 pmol/l#, FGF-234000 pg/ml | Thirst, appetite loss, bilateral ankle pain | Bisphosphonate (zoledronate) |
| 1 | Dürr et al.; BMC Musculoskelet Disord. 2019 Oct 20; 20(1):456 [16] | 7 years, M | Giant cell tumor of bone | 60 mg, 1× in day 8 and 15, then 1/4 weeks, 1 year | Improvement of bone growth and healing of the cyst | 6 months | Not specified | Not specified | Not specified | Intensive care treatment necessary (not specified) |
| 1 | Upfill-Brown et al.; JBMR Plus. 2019; 3:e10210 [11] | 10 years, F | Aneurysmal bone cyst | 120 mg, 2×/month the first month, then 1×/month, total 15 doses | Excellent clinical and radiological response | 5 months | Ca 3.86 mmol/l, iCa 2.0 mmol/l | Not assessed | Severe diffuse abdominal pain, nausea, vomiting | Bisphosphonates, furosemide, calcitonin |
| 4 | Chawla et al.; Lancet Oncol. 2019 dec; 20(12):1719 [17] | 25–46 years, gender not specified | Giant cell tumor of bone |
120 mg, 1× in days 8 and 15, then 1/4 weeks, 6 months |
Study protocol | 1 months | Not specified | Not specified | Not specified | Not specified |
| 1 | Actual case report | 86 years, F | Osteoporosis | 60 mg, 1×/6 months, 3 years | Unknown | 6 months | cCa 3.35 mmol/l, P 0.9 mmol/l | CTX 1777 ng/l, PTH suppressed | Anorexia, acute kidney injury, weight loss, malnutrition, bad health status | Rehydration, cinacalcet, calcitonin, restart DMAb |
DMAb, denosumab; P, phosphate, normal values 0.76–1.41 mmol/l; Ca, calcium; cCa, albumin-corrected calcium, normal values: 2.15–2.50 mmol/l; tCa, total calcium; iCa, ionized calcium, normal values 1.1–1.3 mmol/l; BTMs, bone turnover markers; PTH, parathyroid hormone, normal values 1.3–9.3 pmol/l, #values initially measured in pg/ml, converted into pmol/l; FGF-23, fibroblast growth factor 23, normal values < 50 pg/ml; CTX, C-terminal telopeptide of type I collagen, premenopausal women upper limit: 573 ng/l; P1NP, procollagen type 1 N-telopeptide, premenopausal women upper limit: 20.3–56.3 μg/l; NTX, urinary N-telopeptide of type 1 collagen, normal values 14.3–89.0 nmol BCE/mmol creat (nmol bone collagen equivalents/mmol creatinine)